Synergistic famciclovir and celecoxib combination therapy for functional somatic syndromes

ABSTRACT

The present invention relates to methods of treating fibromyalgia, by administering a therapeutically-effective combination of an antiviral component and a COX-2 inhibitor component. The invention is further related to pharmaceutical compositions comprising a combination of a therapeutically-effective amount of the antiviral compound famciclovir and a therapeutically-effective amount of the COX-2 inhibitor celecoxib. The invention is also related to methods of treating functional somatic syndromes by administering a therapeutically-effective combination of famciclovir and celecoxib.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. Ser. No. 15/597,807 filed on17 May 2017, which is a Continuation of Ser. No. 14/459,905 filed 14Aug. 2014, which is a Continuation Application of U.S. Ser. No.13/761,056 filed 6 Feb. 2013, which claims the benefit of U.S.Provisional Application No. 61/595,507, filed on 6 Feb. 2012. The entiredisclosures of the above applications are incorporated herein byreference.

FIELD

The present invention relates to pharmaceutical compositions and methodsof treating functional somatic syndromes using combination therapies.

BACKGROUND

Fibromyalgia (FM), a common, frequently misdiagnosed systemic disorderthat often presents with irritable bowel syndrome (IBS) and chronicfatigue syndrome (CFS), is generally classified as a functional somaticsyndrome (FSS). While patients with myalgia, fatigue and otherfunctional somatic complaints have been recognized in the medicalliterature for centuries, many physicians believe FM and related FSS tobe nothing more than a psychosomatic condition. Skeptics have evenchallenged the validity of FM as a distinct clinical entity, expressingconcern about the subjective nature of chronic pain, the lack ofstandard laboratory tests and the bias of the tender point (TP)examination. Patients with FM typically experience prolonged periods ofpain accompanied by stiffness. Associated symptoms may also includesleep disturbances, fatigue, cognitive dysfunction, depressive symptoms,headaches, and anxiety. Patients often report the onset of theirsymptoms after a period of substantial physical and/or emotional stress.

There is no gold standard for diagnosing FM and there are currently nolaboratory tests to diagnose the disorder. Diagnosis is based onsymptoms and physical examination. The American College of Rheumatology(ACR) criteria for the classification of FM require the presence ofwidespread pain for at least 3 months involving 4 quadrants of the body,as well as pressure pain on palpation in at least 11 of 18 standardizedanatomical sites. While the etiology and pathogenesis of the disorderare not clearly understood, a combination of interactions among externalstressors, behavioral and psychiatric constructs, neurotransmitters,hormones, immune, and sympathetic nervous systems appears to beinvolved. The initial diagnosis of FM is usually made between the agesof 20 and 50 years. In the United States, an estimated 2% to 4% of thepopulation is affected by FM. Although women comprise 90% of thesepatients, FM also occurs in men and children of all ethnic groups.

The overabundance of complaints, coupled with the time constraints of abusy medical practice frequently overwhelms physicians, resulting infrustrated physicians and antagonized patients. Unfortunately, thesecret to understanding FM may be to evaluate the entire spectrum ofcomplaints. When coupling FM with CFS and IBS, the array of symptoms andsigns is daunting to analyze.

The focus of drug therapy for FM is primarily symptomatic. Traditionaltreatment is multifaceted and includes anti-epileptic medicines such aspregabalin and gabapentin. The U.S. Food and Drug Administration hasalso approved the serotonin and norepinepherine reuptake inhibitorsduloxetine hydrochloride and milnacipran hydrochloride, for managementof FM.

Tricyclic antidepressants, selective serotonin reuptake inhibitors,non-steroidal anti-inflammatory analgesics and muscle relaxers have alsobeen used in the management of FM.

The common strategy of choice for most physicians is to decrease painand to increase function without promoting polypharmacy. Unfortunately,ineffective medical treatment and an excess of prescribed drugs oftenresults in a continued deterioration of the patient's health. Thus thereis a need for new, more effective treatments for patients suffering fromfunctional somatic syndromes.

Use of nimesulide, a selective inhibitor of COX-2, is mentioned in U.S.Patent Application Publication No. 2009/0258947, in combination withother active agents, including anti-viral agents, for use in thetreatment of NSAID indicated disorders such as fibromyalgia.

Use of selective COX-2 inhibitors (e.g., celecoxib, meloxicam), asmentioned in U.S. Patent Application Publication No. 2003/0195242, canbe combined with other compounds known to be effective in reducing butnot eliminating the recurrence of herpesviruses (e.g., acyclovir,famcyclovir, viral thymidine kinase inhibitor and other partiallyeffective HSV recurrence inhibitors), for inhibiting the recurrence of alatent herpesvirus infection, such as recurrent ocular herpeticinfection which is painful.

Use of valacyclovir, as mentioned by Kendall, et al., in J. Rheumatology(2004) 31, 783-784, for treating fibromyalgia patients, was notsuccessful and valacyclovir was not recommended as therapy forfibromyalgia.

Use of valacyclovir is mentioned by Lerner, et al., in In Vivo (2007)21, 707-714, for treating chronic fatigue syndrome in a subset ofpatients with Epstein-Barr virus infection.

Use of a COX-2 inhibitor, as mentioned in U.S. Patent ApplicationPublication No. 2005/0014729, can be combined with one or moredermatologic treatment agents, including antiviral agents (e.g.,acyclovir, famciclovir and valacyclovir), for treating dermatologicaldisorders.

Use of acyclovir and diclofenac (as a permitted analgesic) is mentionedby Genlin, et al., in Anesthesia & Analgesia (2009) 109, 1651-1655, fortreating postherpetic neuralgia in patients with acute herpes zoster.

Use of selective COX-2 inhibitors, in combination with an anti-herpesvirus agent (e.g., acyclovir, famciclovir and valacyclovir), ismentioned in PCT Application Publication No. WO 2004/056349, fortreating a herpes virus infection.

Use of a combination of one or more antiviral agents (e.g., acyclovir,famciclovir) and one or more COX-2 inhibitors is mentioned in U.S.Patent Application Publication No. 2003/0211163, for treating papillomavirus infection.

A multiparticulate osmotic delivery system for modified release of atleast one drug, as described in U.S. Patent Application Publication No.2009/0004281, mentions celecoxib, diclofenac, meloxicam and acyclovir,in a listing of drugs that could be used in the delivery system fortreating of diseases, including fibromyalgia.

A joint enhancing composition, which can contain a second therapeutic,including diclofenac, celecoxib or acyclovir, is mentioned in U.S.Patent Application Publication No. 2006/0240037, for treating jointdisorders, which can include fibromyositis.

A solidifying formulation for dermal delivery of a drug, as mentioned inU.S. Patent Application Publication No. 2007/0196457, can includeacyclovir, famciclovir or valaciclovir for treating herpes viralinfections, and diclofenac and COX-2 selective inhibitors for treatingpain (e.g., back pain, musculoskeletal pain).

Adhesive solidifying formulations for sustained, dermal drug delivery,described in PCT Application Publication WO 2007/070695, mentions use ofacyclovir, famciclovir or valaciclovir for treating herpes viralinfections, and diclofenac and COX-2 selective inhibitors for treatingpain (e.g., back pain, musculoskeletal pain).

A preparation for topical, transdermal localized delivery of therapeuticagents, as mentioned in U.S. Patent Application Publication No.2004/0208914, includes diclofenac, celecoxib and meloxicam for treatingpain and/or inflammation and antiviral agents, such as acyclovir.

A sustained release pharmaceutical composition, as mentioned in U.S.Patent Application Publication No. 2008/0220079, lists celecoxib,meloxicam and diclofenac as analgesic drugs and acyclovir andvalaciclovir as antiviral therapies.

A foamable, vitamin containing composition, as described in U.S. PatentApplication Publication No. 2008/0069779, may contain at least oneadditional therapeutic agent, such as an acyclovir as an antiviralagent, or diclofenac or meloxicam as a non-steroidal anti-inflammatoryagent.

A therapeutic, topical formulation, as mentioned in U.S. PatentApplication Publication No. 2009/0062315, includes use of an NSAID, suchas diclofenac, and an antiviral drug, such as aciclovir, valaciclovirand famciclovir, to treat pain and inflammation caused by herpes virusinfection.

A polymeric foam formulation for topical delivery of a therapeuticagent, described in PCT Application Publication WO 2004/041118, mentionsuse of NSAIDS, such as diclofenac, meloxicam and celecoxib, andantiviral agents, such as acyclovir.

Use of a combination of an antiviral agent (e.g., acyclovir) and anNSAID (e.g., diclofenac), is mentioned in PCT Application Publication WO1998/52540, for treating symptoms of colds and flu (e.g., sore throat).

Use of antimicrobials, including acyclovir and valacyclovir, incombination with an agent that blocks human dormancy and a thirdcomponent to reduce adverse effects, such as a COX-2 inhibitor (e.g.,CELEBREX®), is mentioned in US Patent Application Publication2008/0160007, to treat cancer.

Use of dextromethorphan analogs, in combination with anti-infectiveagents (e.g., acyclovir, valacyclovir) or anti-inflammatory agents(e.g., celecoxib, diclofenac) is mentioned in PCT ApplicationPublication WO 2008/097924, to treat neurological disorders, includingfibromyalgia.

Use of valaciclovir and diclofenac is mentioned in Ogoima, D., PanAfrican Medical Journal (2011) Vol. 9, for treating a patient withdisseminated herpes zoster infection.

Use of acyclovir ophthalmic ointment, intravenous acyclovir and oraldiclofenac, is mentioned by Veraldi, et al., in ActaDermato-Venereologica (1998) 78, 236-237, for treating pain and lesionsin a patient with verrucuos-crusted herpes zoster infection.

SUMMARY

In one embodiment, there is provided a method for treating a subjectsusceptible or to or afflicted with fibromyalgia, the method comprisingadministering to the subject a therapeutically-effective combination ofan antiviral component and a COX-2 inhibitor component, wherein thecombination administered produces no substantial adverse event.

In another embodiment, there is provided a combination comprising atherapeutically-effective amount of famciclovir and atherapeutically-effective amount of celecoxib.

In another embodiment, there is provided a method for treating a subjectsusceptible or to or afflicted with one or more functional somaticsyndrome conditions comprising: fibromyalgia, chronic fatigue syndrome,irritable bowel syndrome, chronic pain, chronic headache, chronic neckpain, chronic back pain, mood disorder, chronic depression, chronicclinical anxiety disorder, post-traumatic stress disorder (PTSD), brainfog, cognitive dysfunction and chronic interstitial cystitis, the methodcomprising administering to the subject a therapeutically-effectivecombination of famciclovir and celecoxib, wherein the combinationadministered produces no substantial adverse event.

In yet another embodiment, there is kit presentation, comprising atherapeutically-effective amount of famciclovir in a first unit dosageform, and a therapeutically-effective amount of celecoxib, in a secondunit dosage form, wherein the first and second unit dosage forms areseparately enclosed in one or more containers, arranged in a singlepackage or dispensing device, optionally comprising directions on how touse kit components suitable for administration to obtain a therapeuticoutcome.

Further areas of applicability will become apparent from the descriptionprovided herein. The description and specific examples in this summaryare intended for purposes of illustration only and are not intended tolimit the scope of the present disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows some, but not all, conditions classified as functionalsomatic syndromes.

FIG. 2 outlines factual and theoretical relationship of stress, HSV-1,and effects created by involvement of the trigeminal, nodose, and sacraldorsal root ganglia.

FIG. 3 outlines the effect of fibromyalgia on the nervous, endocrine andimmune system, showing HSV-1 as the chronic stressor, and indicates theparticular patient symptoms caused by these effects.

FIG. 4 outlines the abnormal stress response that results in faultyamygdala, locus coeruleus, and hypothalamic-pituitary-adrenal axisfunction, showing that HSV-1 is the chronic stressor, and indicates theparticular patient symptoms caused by these effects.

FIG. 5 shows a treatment algorithm for patients suffering from chronicpain, fibromyalgia, chronic fatigue syndrome, other functional somaticsyndromes, and other conditions described herein, using a combination ofan antiviral compound and a COX-2 inhibitor.

DETAILED DESCRIPTION

The following description is merely exemplary in nature and is notintended to limit the present disclosure, application or uses.

A. Definitions

The term “pharmaceutically acceptable” means suitable for use inpharmaceutical preparations, generally considered as safe for such use,officially approved by a regulatory agency of a national or stategovernment for such use, or being listed in the U. S. Pharmacopoeia orother generally recognized pharmacopoeia for use in animals, and moreparticularly in humans.

The term “therapeutically-effective amount” refers to an amount of acompound that, when administered to a subject for treating a disease, issufficient to effect treatment for the disease. “Therapeuticallyeffective amount” can vary depending on the compound, the disease andits severity, the age, the weight, etc. of the subject to be treated.

The term “COX-2 inhibitor” refers to a cyclooxygenase-2 inhibitor, whichis any pharmaceutically acceptable compound that inhibits the enzymecyclooxygenase-2.

The term “COX-1 inhibitor” refers to a cyclooxygenase-1 inhibitor, whichis any pharmaceutically acceptable compound that inhibits the enzymecyclooxygenase-1.

The term “HSV-1” refers to herpes simplex virus-1.

The terms “prevent”, “prevention”, or “preventing” refer to eitherpreventing the onset of preclinically evident condition altogether orpreventing the onset of a preclinical evident stage of a condition in asubject. Prevention includes, but is not limited to, prophylactictreatment of a subject at risk of developing a condition.

The term “treat” (and corresponding terms “treatment” and “treating”)includes palliative, restorative, and preventative treatment of asubject. The term “palliative treatment” refers to treatment that easesor reduces the effect or intensity of a condition in a subject withoutcuring the condition. The term “preventative treatment” (and thecorresponding term “prophylactic treatment”) refers to treatment thatprevents the occurrence of a condition in a subject. The term“restorative treatment” refers to treatment that halts the progressionof, reduces the pathologic manifestations of, or entirely eliminates acondition in a subject.

The term “FM” or “FMS” refer to fibromyalgia and fibromyalgia syndrome,respectively. Fibromyalgia (FM or FMS) is a medical disordercharacterized by chronic widespread pain and other symptoms, includingbut not limited to fatigue, insomnia, depression, allodynia, headaches,irritable bowel syndrome, sensitivity to light, numbness and anxietysymptoms.

The term “CFS” refers to chronic fatigue syndrome. Patients with CFStypically have severe chronic fatigue, not due to ongoing exertion or amedical condition, that significantly interferes with daily activities.

The term “IBS” refers to irritable bowel syndrome. Patients with IBSsuffer abdominal pain at least three times a month, not caused by otherdisease or injury.

The term “cognitive dysfunction”, also referred to as “brain fog”,“mental fog”, or “impaired cognition”, refers to the loss or impairmentof intellectual function (such as thinking, remembering, or reasoning)of sufficient severity to interfere with daily functioning.

The term “mood disorder” or “depression” refers to a person sufferingfrom a depressed mood or loss of interest or pleasure in dailyactivities.

The term “chronic anxiety disorder” and “post-traumatic stress disorder”(PTSD) refer to a person suffering from excessive anxiety and worryabout a variety of events and situations in a way that is more thanwould be expected for the particular situation or event.

The term “chronic headache” refers to a person suffering from a headachelasting from 30 minutes to seven days.

The term “interstitial cystitis” refers to a person suffering frompelvic pain and urinary frequency that is of a chronic nature and oftenunexplained by any known urologic or other system pathology.

The term “chronic pain” refers to a person suffering from persistent,non-acute, sometimes disabling pain in the extremities or other areas ofthe body, often of unknown origin.

The term “FSS”, or “functional somatic syndrome”, refers to syndromestypically characterized by multiple physical symptoms, which are notclearly related to demonstrable tissue abnormalities, including, but notlimited to, chemical sensitivity, repetition stress injury, chronicwhiplash, chronic fatigue syndrome, irritable bowel syndrome,fibromyalgia, chronic pain, chronic headache, chronic neck pain, chronicback pain, chronic depression, chronic clinical anxiety disorder,post-traumatic stress disorder (PTSD), brain fog, cognitive dysfunctionand chronic interstitial cystitis.

The term “GERD” refers to gastroesophageal reflux disease.

The term “guanine analog antiviral agent” and “guanine analog antiviralcompound” refer to antiviral agents, components or compounds which aresynthetic analogs of guanosine which selectively interfere with viralDNA synthesis.

The terms “famcyclovir” and “famciclovir” refer to the same antiviralcompound.

The terms “valacyclovir” and “valaciclovir” refer to the same antiviralcompound.

The terms “acyclovir” and “aciclovir” refer to the same antiviralcompound.

The term “QD” refers to once a day.

The term “BID” refers to two times a day.

The term “TID” refers to three times a day.

The term “QID” refers to four times a day.

The term PO refers to oral administration.

The term “Likert Survey” (and the corresponding term “Likert Scale”)refers to a questionnaire which asks subjects the extent to which theyagree or disagree with a statement, using a five-point scale.

The term “combination therapy” (or “co-therapy”), in defining use of anantiviral compound and a COX-2 inhibitor, as described herein, isintended to embrace administration of each agent in a sequential mannerin a regimen that will provide beneficial effects of the drugcombination, and is intended as well to embrace co-administration ofthese agents in a substantially simultaneous manner, such as by oralingestion of a single capsule having a fixed ratio of these activeagents or ingestion of multiple, separate capsules for each agent.“Combination therapy” will also include simultaneous or sequentialadministration by intravenous, intramuscular or other parenteral routesinto the body, including direct absorption through mucous membranetissues, as found in the sinus passages. Sequential administration alsoincludes drug combination where the individual elements may beadministered at different times and/or by different routes but which actin combination to provide a beneficial effect. It is expected that thiscombination therapy of an antiviral compound and a COX-2 inhibitor willresult in co-action of the antiviral compound and the COX-2 inhibitor,providing a pharmacokinetic interaction, or a pharmacodynamicinteraction, or both, where the compounds are administered eithersimultaneously or sequentially, to permit such co-action.

The term “substantial adverse event”, as used, for example, in “nosubstantial adverse event”, refers to one or more unfavorable signs,including one or more abnormal laboratory findings, symptoms or diseaseconditions associated with the use of a medical treatment or procedurein a subject, that results in a subject's death or risk of dying,hospitalization, permanent damage, disability or impairment of abilityto perform one or more daily activities. Examples of impairment of oneor more daily activities, as a result of a “substantial adverse event”,include being bedridden, unable to perform work at a sedentary job,unable to care for oneself, drive a car or perform housekeeping chores.Causative effects that could produce a substantial adverse eventinclude, for example, headaches, dizziness, palpitations, fainting,vomiting and dehydration.

B. Clinical Observations

The present invention is to be understood as embracing treatment offunctional somatic syndromes (FSS), including but not limited tofibromyalgia, as well as pain and associated functional symptomsassociated with fibromyalgia. Patients with fibromyalgia were observedto display a variety of symptoms, including but not limited to fatigue,insomnia, depression, allodynia, headaches, irritable bowel syndrome,sensitivity to light, numbness and anxiety. Stress often exacerbates thesymptoms. While the etiology and pathogenesis of FSS is not clearlyunderstood, a combination of interactions among external stressors,neurotransmitters, hormones, the immune system, and the sympatheticnervous system, appear to be involved.

Earlier studies, evaluating patients with chronic gastrointestinaldisorders (W. L. Pridgen and E. Haggard, “Biliary and GastrointestinalManifestations of the Herpes Simplex Virus, Type I (HSV-I)”,http://tuscaloosasurgery.com/pdf/biliary-gastroherpes-simplex-ibs-final-copy.pdf),a spectrum of disorders were observed, including functional somaticsyndromes such as fibromyalgia, and chronic fatigue syndrome. Based onthis experience, it is hypothesized that HSV-1 plays a major role infibromyalgia and related functional somatic syndromes.

The worldwide prevalence rate of HSV-1 is reported to be 98%. Theprimary target cells are epithelial cells of mucocutaneous membranes. Inthese cells, HSV-1 replicates efficiently and causes cell lysis.Following the initial replication at the site of entry, the virus gainsaccess to the sensory neurons in the nucleus of the nerve cell bodieswhere it remains in a state known as latency (see FIG. 2). Primaryinfection with HSV-1 generally occurs in childhood or early adolescencefollowing inoculation via the eyes, nose, or oral mucosa, or the genitaltract. It is less well known that inoculation can also take placethrough the GI tract. The virus is then transported to the nerve cellnucleus located in the sensory ganglia. Gesser and Koo demonstratedinvolvement of the ganglion of the vagus nerve (nodose ganglion). Theypostulated a potential for apoptotic destruction of the ganglion overtime [R. Gesser and S. Koo, J. Virol. 70, 4097-4102 (1996)], [R. Gesserand S. Koo, J. Virol. 71, 4103-4106 (1997)]. Human studies proved thepresence of only HSV-1 in the neurons of the mesenteric, submucosal, andperiglandular plexuses of the esophagus, stomach, and duodenum. In thesestudies the spread was specific to the nerve inoculation site ratherthan that of the circulatory system. The fibers that originated in thenodose ganglion, ultimately terminated centrally in the nucleus tractussolitarius (NTS) [R. Gesser and S. Koo, J. Virol. 71, 4103-4106 (1997)].Based on the observed development of erosive esophagitis and gastriculcers in mice, they noted that these ulcers were not directly infected,but were found to overlie virus-infected enteric ganglia. Gesser and Koopostulated that HSV-1 infection of the enteric nervous system is acausal agent in the pathogenesis of chronic recurrent functional humangastrointestinal disorders [R. Gesser and S. Koo, J. Virol. 70,4097-4102 (1996)], [R. Gesser and S. Koo, J. Virol. 71, 4103-4106(1997)].

Herpes viruses are unique because they remain dormant until conditionsare sufficient for a reactivation. The stressors in this process mayinitiate the synthesis and release of peptides and hormones of thesympathetic nervous system and the hypothalamic-pituitary-adrenal axis.Most viruses in this class rarely reactivate. Only two viruses in thisfamily reactivate often enough to create the milieu needed for a chronicdebilitating process. We found no evidence for HSV-2 to be the offendingorganism as it cycles only once or twice a year. Only HSV-1 cyclesfrequently enough, on average 4 times a year, yet occasionally as oftenas monthly, to result in the slowly debilitating illnesses. We theorizethat after many reactivations, a neuronal cell body dies due toapoptosis and that the ganglion undergoes destruction in the regionsgoverning the first inoculation site.

The existence of HSV-1 in one or more ganglia may directly or indirectlyaffect the central nervous system (CNS), hypothalamic pituitary axes(HPA) and immune system (FIG. 3). Dysregulation of pain processingwithin the CNS may lead to an amplified perception of pain and othersensory stimuli. This phenomenon, often referred to as centralsensitization or augmentation, results from changes in the properties ofneurons in the CNS where pain is no longer coupled, as acute nociceptivepain is, to the presence, intensity, or duration of noxious peripheralstimuli. Neurotransmitters such as glutamate, Substance P, serotonin,norepinephrine, dopamine, brain-derived neurotrophic factor (BDNF) andgamma aminobutyric acid (GABA), are activated in chronic pain anddepression. Substance P, cerebrospinal fluid levels and serumconcentration of brain-derived neurotrophic factor have beenconsistently higher in patients with fibromyalgia compared withcontrols. Patients with fibromyalgia also have an abnormal dopamineresponse to pain. Recent data suggest a putative role ofpro-inflammatory cytokines, including interleukin-1-beta, tumor necrosisfactor-alpha (TNFα), IL-6 and IL-8, in the pathogenesis of fibromyalgiaand the modulation of symptoms [M. DiFranco, et al., Ann. N. Y. Acad.Sci. 1193(1), 84-90 (2010)]. Hence pain, as the defining characteristicof fibromyalgia, is not due to tissue damage or inflammation and is thusfundamentally different from rheumatic disorders and many other painconditions as these conditions cause inflammation in the joints andtissues. HSV-1 has developed various immune evasion mechanisms whichprove to be a particular challenge for the immune system. Cytokines andcytokine-induced genes are important for the ability of any organism toraise an antiviral response. Understanding the immune mediators andtheir possible role in fibromyalgia may be the most daunting obstaclesin understanding the disorder. Gur and Oktayoglu [A. Gur and P.Oktayoglu, Curr. Pain Headache Rep. 12(3), 175-181 (2008)] explain howcytokines related to acute or repetitive tissue injuries may beresponsible for long-term activation of spinal cord glia and dorsal hornneurons, thus resulting in central sensitization. The immune systemresponds to stressors by causing certain immune cells to secrete thepro-inflammatory cytokines IL-1 and IL-6. Both cytokines are involved ininflammation, and IL-6 is thought to worsen the symptoms of autoimmunedisease and fibromyalgia [L. Vanderhaeghe, Total Health 23, 34-35(2001)].

IL-6 and TNFα are increased in autoimmune disorders, osteoporosis,over-exercise, fibromyalgia and osteoarthritis [A. Gur, et al., J.Rheumatol. 29, 358-361 (2002)]. The neuroendocrine system (NS) andcytokines also figure in the course of fibromyalgia. The NS responds tostress by activating the HPA-axis. Individuals who have reduced HPA-axisactivity often have symptoms of fatigue, depressed mood, myalgias anddisturbed sleep. Increased glucocorticoid levels may be related toreduced fatigue and increased wellbeing and energy. Stimulation of thehypothalamus with IL-6 showed delayed adrenocorticotropic hormone (ACTH)responsiveness in fibromyalgia [D. Torpy, et al., Arthritis Rheum. 43,872-880 (2000)]. Cytokines, such as IL-1b, IL-6 and TNFα have been shownto contribute directly to central and peripheral neuropathic pain [D.Wallace, Curr. Pharm. Des. 12, 17-22 (2006)].

Fibromyalgia patients often have little motivation to eat, are listless,complain of fatigue and malaise, lose interest in social activities, andhave significant changes in sleep patterns. They also are unable toexperience pleasure, have exaggerated responses to pain and cannotconcentrate. In patients with fibromyalgia, the level of pain intensitycan be related to the spinal fluid level of arginine a precursor tonitric oxide [K. Kelley, et al., Brain Behay. Immun. 17, 5112-5118(2003)]. Wallace postulated that activation of glial cells in the brainand spinal cord by substances known to be involved with chronic painleads to release of IL-1, IL-6, nerve growth factor, NMDA, and SubstanceP which further perpetuates pain and flu-like symptoms [D. Wallace,Curr. Pharm. Des. 12, 17-22 (2006)].

There are lower levels of IL-4 and IL-10 in patients with chronic pain.Chronic pain (dull, aching, or burning) is believed to be transmittedthrough unmyelinated C fibers to dorsal horn nociceptive neurons. Thesynapses use glutamate as a neurotransmitter. Nitric oxide promotes theexaggerated release of excitatory amino acids and Substance P frompresynaptic afferent terminals and causes the dorsal horn to becomehyper-excitable [K. Kelley, et al., Brain Behay. Immun. 17, 5112-5118(2003)].

Nociception, neural processing of noxious stimuli, is also thought toplay a role in fibromyalgia (FIG. 4). The locus coeruleus is a nucleusin the brain stem involved in mediating sympathetic effects duringstress, specifically the synthesis and release of norepinephrine.Fibromyalgia patients are much more sensitive to windup pain, whichincreases with repetitive stimuli. The locus coeruleus also innervatesthe amygdala, involved in the emotional processing of pain. This nucleusalso innervates the hypothalamus, activating thehypothalamo-pituitary-adrenal axis, stimulating secretion ofcorticotropin-releasing factor causing release of adrenocorticotropichormone from the anterior pituitary, increasing cortisol synthesis inthe adrenal glands.

Growth hormone deficiency has also been observed in some fibromyalgiapatients. Since some symptoms of growth hormone deficiency are similarto those observed in fibromyalgia (e.g., fatigue, depression, muscleweakness, impaired memory) it is believed that growth hormone deficiencymay contribute to the pathophysiology of fibromyalgia. Defective growthhormone secretion in fibromyalgia patients may result from increasedrelease of somatostatin by the hypothalamus.

Various studies confirm that isoforms of COX-1 and COX-2 are criticalfor efficient viral replication. In one study Ray and Enquist showedthat simultaneous inhibition of COX-1 and COX-2 caused a dramaticreduction of viral yield after HSV-1 infection [N. Ray and L. Enquist,J. Virol. 78, 3489-3501 (2004)]. Hill, et al., used microarrays toanalyze gene expression in the trigeminal ganglion of mice infected withlatent HSV-1, and found COX-2 gene expression significantly up regulatedafter reactivation [J. Hill, et al., Virus Genes 23, 273-280 (2001)].Gebhardt reported that the selective COX-2 inhibitor celecoxib cansuppress hyperthermic stress-induced herpes viral reactivation in thenervous system of mice [B. Gebhardt, et al., J. Ocul. Pharmacol. Ther.21, 114-120 (2005)].

Functional somatic syndromes (FSS) may be defined as conditions“characterized by patterns of persistent bodily complaints for whichadequate examination does not reveal sufficiently explanatory structuralor other specified pathology” [P. Henningsen, et al. (2007) Lancet 369,946-954]. A diverse number of conditions are commonly described as FSS,including: fibromyalgia, irritable bowel syndrome, chronic fatiguesyndrome, premenstrual syndrome, non-ulcer dyspepsia, chronic pain,chronic pelvic pain, hypoglycemia, low back pain, sick buildingsyndrome, Gulf War syndrome, tension headache, tempo-mandibular jointdisorder, repetitive strain injury, multiple chemical sensitivity,interstitial cystitis, chronic Lyme disease, depression, post-traumaticstress disorder (PTSD), chronic anxiety disorder, food hypersensitivityand brain fog or cognitive dysfunction.

Despite the broad range of FSS conditions, these disease states may havea common etiology, rather than being distinct syndromes. Wessely andcolleagues concluded on the basis of a literature review that there wassubstantial overlap between these conditions and that their similaritieswere greater than their differences, proposing the concept of a generalfunctional somatic syndrome [S. Wessely, et al. (1999) Lancet 354,936-939].

A common etiology for FSS was also explored by Bland, who pointed outthat when the allostatic load, the combined external and internalstress, exceeds the ability of the patient to maintain allostasis,alterations in function occur giving rise to symptomatic FSS [J. Bland(2008) Alt. Therapies 14, 14-16.]

The rationale for the combination therapy described herein, where it ishypothesized that HSV-1 plays a major causal role in fibromyalgia andother FSS, is based in part on the discovery that the combination of anantiviral compound and a COX-2 inhibitor will increase efficacy in thetreatment of these conditions (see Example A).

Additional support for the concept that HSV-1 is a common etiologicalstressor that gives rise to FSS is provided in the following biopsystudies:

Study Protocol I: HSV-1 DNA and EM Analysis of Human GastrointestinalMucosa

Study Purpose:

A number of gastrointestinal (GI) disorders are frequently co-morbidwith functional somatic syndromes (FSS) such as but not limited tofibromyalgia and chronic fatigue syndrome. We hypothesize that herpessimplex virus type 1 (HSV-1) plays a major role in the chronicgastrointestinal (GI) disorders associated with FSS. This study usesvirus-specific DNA amplification/sequencing, herpesvirus-specificantibodies to demonstrate active infection (immunoblot) and electronmicroscopy (EM) to demonstrate the presence of the virus in GI biopsiesfrom chronically ill patients who present with both fibromyalgia and anassociated GI disorder.

Study Procedure:

In ongoing studies, GI specimens (biopsies) were collected fromfibromyalgia patients who are undergoing their routine endoscopicwork-up for GI disease. Test samples were obtained from patients thatpresent with both GI disease and fibromyalgia. The specimens weredivided, with one part used for medical/diagnostic purposes (sent topathology) and the other part used for this study.

PCR (polymerase chain reaction) with universal herpesvirus primers wereused to amplify any herpesvirus DNA present in the biopsy samples.Herpesvirus DNA was sequenced to determine which herpesvirus was presentin the tissue samples. Quantitative PCR using primers specific to theidentified herpesvirus was performed to measure and compare theinfection levels in test and control samples. Using an antibody specificto a herpesvirus protein produced in infected cells, immunoblot assayswere done to determine whether active infection was underway in thebiopsied tissue at the time of collection. In subsequent studies,electron microscopy will be performed to reveal the presence ofherpesvirus particles in the tissue samples.

The study population includes both men and women ages 19-75 years thatsuffer from chronic gastrointestinal illnesses. These illnesses include,but are not limited to GERD, irritable bowel syndrome (IBS), colonicinertia, gastroparesis, gastritis, recurrent pancreatitis, and pepticulcer disease.

Results: 19 fibromyalgia patient tissue biopsies have been tested forthe presence of herpesvirus DNA. All but one (18 out of 19 samples) werefound to contain herpesvirus DNA. In analyzing the sequences of theherpesvirus DNA found in these 18 samples, all contained only HSV-1 DNA(no other herpesvirus DNA was present). The presence of HSV-1 DNA in thetissue samples is a strong indicator of HSV-1 infection.

It is possible that HSV-1 DNA could be present in a tissue samplewithout active infection due to the presence of HSV-1 virus particlespassing through the GI tract of the patient at the time of biopsycollection. Although this is unlikely to have occurred in all 18 samplesthat were positive for HSV-1 DNA, a more definitive test was performedfor the presence of active HSV-1 infection in the tissue samplescollected. In this test, an immunoblot is performed using an antibodyspecific to a viral protein (ICP8) that is present in virally infectedcells, but is not present in free virus particles. Of the 9 positivebiopsies examined with immunoblot, 8 were positive for the presence ofICP8, showing active HSV-1 infection was occurring in the GI tracts ofthese patients at the time of biopsy collection.

# of samples # of positive Test performed/Question asked tested samplesPCR: Is a herpesvirus present 19 18 in the tissue? DNA sequencing: Isthe herpesvirus 18 18 present in the tissue HSV-1? ICP8 immunoblot: Isactive HSV-1 9 8 infection present in the tissue? Study Protocol II:Herpesvirus DNA, Protein and Electron Microscopic Analysis of HumanGenitourinary Mucosa

Study Purpose:

It is hypothesized that herpes simplex virus type 1 (HSV-1) plays amajor role in some genitourinary (GU) disorders. This study will usevirus-specific detection via DNA amplification/sequencing,immunoblotting, and electron microscopy (EM) to demonstrate the presenceof the virus in GU biopsies from chronically ill patients who presentwith interstitial cystitis.

Study Procedure:

GU specimens (biopsies) will be collected from patients who areundergoing their routine endoscopic work-up. Test samples will beobtained from patients that present with interstitial cystitis disease.Control samples will be obtained from patients that present with GUdisorders unrelated to interstitial cystitis. The specimen will bedivided, with one part used for medical/diagnostic purposes (sent topathology) and the other part used for this study.

PCR (polymerase chain reaction) with universal herpesvirus primers willbe used to amplify any herpesvirus DNA present in the biopsy samples.Herpesvirus DNA will be sequenced to determine which herpesvirus ispresent in the tissue samples. Quantitative PCR using primers specificto the identified herpesvirus will be performed to measure and comparethe infection levels in test and control samples. Immunoblots using anantibody specific to a herpesvirus protein found in infected cells willbe performed to verify active infection. When sample size permits,electron microscopy will be performed to reveal the presence ofherpesvirus particles in the tissue samples.

The study sample size is 15 test and 7 control subjects. The studypopulation will include both men and women ages 19-75 years that sufferfrom interstitial cystitis disease.

Results:

These studies will:

-   -   1) determine the presence/absence of herpesvirus DNA in test        tissue and control samples,    -   2) identify the herpesvirus present in test and control samples,        and    -   3) determine if virus numbers are significantly greater in test        samples than in control samples.

C. Pharmaceutical Compositions

In one embodiment there is provided a pharmaceutical composition,comprising a pharmaceutically acceptable carrier in combination with atherapeutically-effective amount of an antiviral compound and atherapeutically-effective amount of a COX-2 inhibitor, in a weight ratiorange from about one-to-one to about five hundred-to-one of theantiviral compound to the COX-2 inhibitor.

In another embodiment there is provided a pharmaceutical composition,comprising a pharmaceutically acceptable carrier in combination with atherapeutically-effective amount of an antiviral compound and atherapeutically-effective amount of a COX-2 inhibitor, in a weight ratiorange from about one-to-one to about one hundred-to-one of the antiviralcompound to the COX-2 inhibitor.

In another embodiment there is provided a pharmaceutical composition,comprising a pharmaceutically acceptable carrier in combination with atherapeutically-effective amount of an antiviral compound and atherapeutically-effective amount of a COX-2 inhibitor, in a weight ratiorange from about one-to-one to about fifty-to-one of the antiviralcompound to the COX-2 inhibitor.

In another embodiment there is provided a pharmaceutical composition,comprising a pharmaceutically acceptable carrier in combination with atherapeutically-effective amount of an antiviral compound and atherapeutically-effective amount of a COX-2 inhibitor, in a weight ratiorange from about one-to-one to about twenty-to-one of the antiviralcompound to the COX-2 inhibitor.

In another embodiment there is provided a pharmaceutical composition,comprising a pharmaceutically acceptable carrier in combination with atherapeutically-effective amount of an antiviral compound and atherapeutically-effective amount of a COX-2 inhibitor, in a weight ratiorange from about one-to-one to about five-to-one of the antiviralcompound to the COX-2 inhibitor.

The compounds of the present invention can be administered in a unitdosage from. If desired, multiple doses per day of the unit dosage formcan be used to increase the total daily dose.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the amount of antiviral compound is present ina unit dosage form from about 250 mg to about 2000 mg.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the amount of antiviral compound is present ina unit dosage form from about 250 mg to about 1000 mg.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the amount of antiviral compound is present ina unit dosage form from about 250 mg to about 500 mg.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the antiviral compound is a guanine analogantiviral compound.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the antiviral compound is selected from thegroup consisting of famciclovir, valacyclovir and acyclovir.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the antiviral compound is famciclovir.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the amount of famciclovir is present in a unitdosage form from about 250 mg to about 1000 mg.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the antiviral compound is valacyclovir.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the amount of valacyclovir is present in aunit dosage form from about 1000 mg to about 2000 mg.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the antiviral compound is acyclovir.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the amount of acyclovir is present in a unitdosage form from about 400 mg to about 1600 mg.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the amount of COX-2 inhibitor is present in aunit dosage form from about 7.5 mg to about 600 mg.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the amount of COX-2 inhibitor is present in aunit dosage form from about 15 mg to about 300 mg.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the amount of COX-2 inhibitor is present in aunit dosage form from about 50 mg to about 200 mg.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the COX-2 inhibitor is selected from the groupconsisting of celecoxib, meloxicam and a diclofenac—misoprostolcombination.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the COX-2 inhibitor is celecoxib.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the amount of celecoxib is present in a unitdosage form from about 50 mg to about 600 mg.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the COX-2 inhibitor is meloxicam.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the amount of meloxicam is present in a unitdosage form from about 7.5 mg to about 15 mg.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the COX-2 inhibitor is adiclofenac—misoprostol combination.

In another embodiment there is provided a pharmaceutical composition, asdescribed herein, wherein the amount of diclofenac is present in a unitdosage form from about 50 mg to about 200 mg and the amount ofmisoprostol is present in a unit dosage form from about 200 μg to about800 μg.

In one embodiment there is provided a combination, comprising atherapeutically-effective amount of famciclovir and atherapeutically-effective amount of celecoxib, wherein the amount offamciclovir is present in a unit dosage form from about 125 mg to about1000 mg, and wherein the amount of celecoxib is present in a unit dosageform from about 100 mg to about 800 mg.

In another embodiment there is provided a combination, as describedherein, wherein the amount of famciclovir is present in a unit dosageform from about 125 mg to about 500 mg.

In another embodiment there is provided a combination, as describedherein, wherein the amount of famciclovir is present in a unit dosageform from about 500 mg to about 1000 mg.

In another embodiment there is provided a combination, as describedherein, wherein the amount of famciclovir is present in a unit dosageform selected from the group consisting of about 125 mg, about 250 mg,about 500 mg and about 1000 mg.

In another embodiment there is provided a combination, as describedherein, wherein the amount of famciclovir is present in a unit dosageform of about 250 mg or about 500 mg.

In another embodiment there is provided a combination, as describedherein, wherein the amount of celecoxib is present in a unit dosage formfrom about 100 mg to about 400 mg.

In another embodiment there is provided a combination, as describedherein, wherein the amount of celecoxib is present in a unit dosage formfrom about 400 mg to about 800 mg.

In another embodiment there is provided a combination, as describedherein, wherein the amount of celecoxib is present in a unit dosage formselected from the group consisting of about 100 mg, about 200 mg, about400 mg and about 800 mg.

In another embodiment there is provided a combination, as describedherein, wherein the amount of celecoxib is present in a unit dosage formof about 200 mg or about 400 mg.

In another embodiment there is provided a combination, as describedherein, wherein the amount of famciclovir is present in a unit dosageform of about 250 mg or about 500 mg, and wherein the amount ofcelecoxib is present in a unit dosage form of about 200 mg or about 400mg.

In one embodiment there is provided a kit presentation, comprising atherapeutically-effective amount of famciclovir in a first unit dosageform, and a therapeutically-effective amount of celecoxib, in a secondunit dosage form, wherein the first and second unit dosage forms areseparately enclosed in one or more containers, arranged in a singlepackage or dispensing device, optionally comprising directions on how touse kit components suitable for administration to obtain a therapeuticoutcome.

In another embodiment there is provided a kit presentation, as describedherein, wherein the amount of famciclovir is present in a unit dosageform from about 125 mg to about 1000 mg, and wherein the amount ofcelecoxib is present in a unit dosage form from about 100 mg to about800 mg.

In another embodiment there is provided a dosage form wherein the amountof drug present may be from about 0.05% to about 95% by weight, moretypically from about 2% to about 50% by weight of the dosage form.

For the treatment of the conditions referred to herein, the compoundsdescribed herein can be administered as follows:

Oral Administration

The compounds of the present invention may be administered orally,including by swallowing, so that the compound enters thegastrointestinal tract, or absorbed into the blood stream directly fromthe mouth (e.g., buccal or sublingual administration).

Suitable compositions for oral administration include solid formulationssuch as tablets, lozenges and capsules, which can contain liquids, gels,or powders.

Compositions for oral administration may be formulated as immediate ormodified release, including delayed or sustained release, optionallywith enteric coating.

Liquid formulations can include solutions, syrups and suspensions, whichcan be used in soft or hard capsules. Such formulations may include apharmaceutically acceptable carrier, for example, water, ethanol,polyethylene glycol, cellulose, or an oil. The formulation may alsoinclude one or more emulsifying agents and/or suspending agents.

Tablets may contain a disintegrant, comprising from about 0.5% to about35% by weight, more typically from about 2% to about 25% of the dosageform. Examples of disintegrants include methyl cellulose, sodium orcalcium carboxymethyl cellulose, croscarmellose sodium,polyvinylpyrrolidone, hydroxypropyl cellulose, starch and the like.

Suitable lubricants, for use in a tablet, may be present in amounts fromabout 0.1% to about 5% by weight, and include calcium, zinc or magnesiumstearate, sodium stearyl fumarate and the like.

Suitable binders, for use in a tablet, include gelatin, polyethyleneglycol, sugars, gums, starch, hydroxypropyl cellulose and the like.Suitable diluents, for use in a tablet, include mannitol, xylitol,lactose, dextrose, sucrose, sorbitol and starch.

Suitable surface active agents and glidants, for use in a tablet, may bepresent in amounts from about 0.1% to about 3% by weight, and includepolysorbate 80, sodium dodecyl sulfate, talc and silicon dioxide.

Parenteral Administration

Compounds of the present invention may be administered directly into theblood stream, muscle, or internal organs. Suitable means for parenteraladministration include intravenous, intra-muscular, subcutaneousintraarterial, intraperitoneal, intrathecal, intracranial, and the like.Suitable devices for parenteral administration include injectors(including needle and needle-free injectors) and infusion methods.

Compositions for parenteral administration may be formulated asimmediate or modified release, including delayed or sustained release.

Most parenteral formulations are aqueous solutions containingexcipients, including salts, buffering agents and carbohydrates.

Parenteral formulations may also be prepared in a dehydrated form (e.g.,by lyophilization) or as sterile non-aqueous solutions. Theseformulations can be used with a suitable vehicle, such as sterile water.Solubility-enhancing agents may also be used in preparation ofparenteral solutions.

Topical Administration

Compounds of the present invention may be administered topically to theskin or transdermally. Formulations for this topical administration caninclude lotions, solutions, creams, gels, hydrogels, ointments, foams,implants, patches and the like. Pharmaceutically acceptable carriers fortopical administration formulations can include water, alcohol, mineraloil, glycerin, polyethylene glycol and the like. Topical administrationcan also be performed by electroporation, iontophoresis, phonophoresisand the like.

Compositions for topical administration may be formulated as immediateor modified release, including delayed or sustained release.

Kits

Compound combinations of the present invention, wherein component A isan antiviral compound and component B is a COX-2 inhibitor as describedherein, can be provided in a kit presentation, comprising an arrangementof components A and B in association with each other, as in a singlepackage or in a drug dispensing device. Such kit presentations, used bya patient, may be dispensed by a hospital-formulary, retail pharmacist,or prescribing-physician.

In one example, the kit may comprise a single package, withtherapeutically-effective doses of components A and B, in the form oftablets or capsules in separate containers (e.g., bottles) heldseparately, as in a tray, and bound together in a single package using,for example, shrink wrap, tape, or a plastic or cardboard box enclosingthe components.

In another example, separate, therapeutically-effective doses ofcombination components A and B, in the form of tablets or capsules, maybe presented as co-packaged, in a single blister pack.

In another example, the kit presentation may providetherapeutically-effective doses of combination components A and B, inthe form of tablets or capsules, which are co-dispensed from a devicewhich delivers the components from a storage receptacle using, forexample, one or more levers to co-dispense individual dose forms ofcomponents A and B to be administered in combination.

The kit presentation may also be used for parenteral administration ofdose forms of Components A and B. For example, individual doses ofcomponents A and B in the form of lyophilized powders, either separatelyor with components A and B mixed together in therapeutically-effectivedoses, arranged in a package also comprising separately contained vialsof sterile water or buffer solution, and optionally a sterile packagedsyringe for administration of the dose combination followingdissolution.

The kit presentation may further comprise directions, in compliance withapproved instructions from a government agency (e.g., U.S. FDA), on howto use the kit components suitable for administration to obtain atherapeutic outcome.

D. Methods of Treatment

The present disclosure further provides for treating a condition in asubject having or susceptible to having such a condition, byadministering to the subject a therapeutically-effective amount of thecompounds as described above. In one embodiment, the treatment ispreventative treatment. In another embodiment, the treatment ispalliative treatment. In another embodiment, the treatment isrestorative treatment.

In one embodiment there is provided a method to treat a subjectsusceptible to or afflicted with a condition selected from the groupconsisting of fibromyalgia, chronic fatigue syndrome, irritable bowelsyndrome, chronic pain, chronic headache, chronic neck pain, chronicback pain, chronic depression, chronic clinical anxiety disorder,post-traumatic stress disorder (PTSD), brain fog, cognitive dysfunctionand chronic interstitial cystitis, the method comprising administeringto the subject a therapeutically-effective amount of an antiviralcompound and a therapeutically-effective amount of a COX-2 inhibitor, ina dose weight ratio range from about one-to-one to about fivehundred-to-one of the antiviral compound to the COX-2 inhibitor.

In another embodiment there is provided a method, as described herein,wherein the dose weight ratio range is from about one-to-one to aboutone hundred-to-one of the antiviral compound to the COX-2 inhibitor.

In another embodiment there is provided a method, as described herein,wherein the dose weight ratio range is from about one-to-one to aboutfifty-to-one of the antiviral compound to the COX-2 inhibitor.

In another embodiment there is provided a method, as described herein,wherein the dose weight ratio range is from about one-to-one to abouttwenty-to-one of the antiviral compound to the COX-2 inhibitor.

In another embodiment there is provided a method, as described herein,wherein the dose weight ratio range is from about one-to-one to aboutfive-to-one of the antiviral compound to the COX-2 inhibitor.

In another embodiment there is provided a method, as described herein,wherein the condition is a combination of fibromyalgia, chronic fatiguesyndrome and irritable bowel syndrome, coexistent in the subject.

In another embodiment there is provided a method, as described herein,wherein the amount of antiviral compound is present in a unit dosageform from about 250 mg to about 2000 mg.

In another embodiment there is provided a method, as described herein,wherein the amount of antiviral compound is present in a unit dosageform from about 250 mg to about 1000 mg.

In another embodiment there is provided a method, as described herein,wherein the amount of antiviral compound is present in a unit dosageform from about 250 mg to about 500 mg.

In another embodiment there is provided a method, as described herein,wherein the antiviral compound is a guanine analog antiviral compound.

In another embodiment there is provided a method, as described herein,wherein the antiviral compound is selected from the group consisting offamciclovir, valacyclovir and acyclovir.

In another embodiment there is provided a method, as described herein,wherein the antiviral compound is famciclovir.

In another embodiment there is provided a method, as described herein,wherein the amount of famciclovir is present in a unit dosage form fromabout 250 mg to about 1000 mg.

In another embodiment there is provided a method, as described herein,wherein the antiviral compound is valacyclovir.

In another embodiment there is provided a method, as described herein,wherein the amount of valacyclovir is present in a unit dosage form fromabout 1000 mg to about 2000 mg.

In another embodiment there is provided a method, as described herein,wherein the antiviral compound is acyclovir.

In another embodiment there is provided a method, as described herein,wherein the amount of valacyclovir is present in a unit dosage form fromabout 400 mg to about 1600 mg.

In another embodiment there is provided a method, as described herein,wherein the amount of COX-2 inhibitor is present in a unit dosage formfrom about 7.5 mg to about 600 mg.

In another embodiment there is provided a method, as described herein,wherein the amount of COX-2 inhibitor is present in a unit dosage formfrom about 15 mg to about 300 mg.

In another embodiment there is provided a method, as described herein,wherein the amount of COX-2 inhibitor is present in a unit dosage formfrom about 50 mg to about 200 mg.

In another embodiment there is provided a method, as described herein,wherein the COX-2 inhibitor is selected from the group consisting ofcelecoxib, meloxicam and a diclofenac—misoprostol combination.

In another embodiment there is provided a method, as described herein,wherein the COX-2 inhibitor is celecoxib.

In another embodiment there is provided a method, as described herein,wherein the amount of celecoxib is present in a unit dosage form fromabout 50 mg to about 600 mg.

In another embodiment there is provided a method, as described herein,wherein the COX-2 inhibitor is meloxicam.

In another embodiment there is provided a method, as described herein,wherein the amount of meloxicam is present in a unit dosage form fromabout 7.5 mg to about 15 mg.

In another embodiment there is provided a method, as described herein,wherein the COX-2 inhibitor is a diclofenac—misoprostol combination.

In another embodiment there is provided a method, as described herein,wherein the amount of diclofenac is present in a unit dosage form fromabout 50 mg to about 200 mg and the amount of misoprostol is present ina unit dosage form from about 200 μg to about 800 μg.

In another embodiment there is provided a method, as described herein,wherein the method further comprises increasing the daily dose of theantiviral compound to 1.5 to 3 times the daily dose, for a period of notmore than five days following onset of an episode of increased symptomsrelated to fibromyalgia, chronic fatigue syndrome or irritable bowelsyndrome.

In another embodiment there is provided a method, as described herein,wherein the method further comprises increasing the daily dose of theCOX-2 inhibitor to 1.5 to 3 times the daily dose, for a period of notmore than five days following onset of an episode of increased symptomsrelated to fibromyalgia, chronic fatigue syndrome or irritable bowelsyndrome.

In another embodiment there is provided a method, as described herein,wherein the method results in a reduction in the administration of atleast one additional therapeutic compound previously administered to thesubject.

In another embodiment there is provided a method, as described herein,wherein the method results in a reduction in the administration of atleast one additional therapeutic compound previously administered to thesubject selected from the group consisting of gabapentin, clonazepam,pregabalin, duloxetine, milnacipran, amitriptyline, fluoxetine,tramadol, morphine, sleep aids and muscle relaxers.

In another embodiment there is provided a method, as described herein,wherein the subject is susceptible to or infected with an HSV-1 virus,wherein the HSV-1 virus infection causes a condition selected from thegroup consisting of fibromyalgia, chronic fatigue syndrome, irritablebowel syndrome, chronic pain, chronic headache, chronic neck pain,chronic back pain, chronic depression, chronic clinical anxietydisorder, post-traumatic stress disorder (PTSD), brain fog, cognitivedysfunction and chronic interstitial cystitis, the method comprisingadministering to the subject a therapeutically-effective amount of anantiviral compound and a therapeutically-effective amount of a COX-2inhibitor, in a dose weight ratio range from about one-to-one to aboutfive hundred-to-one of the antiviral compound to the COX-2 inhibitor.

In another embodiment there is provided a method, as described herein,wherein the combination therapy is administered chronically orcontinuously over long periods of time (months to years). Chronictherapy with antiviral compounds alone is usually avoided because it canincrease the incidence of adverse effects. In addition, prolongedtreatment with antiviral compounds alone can induce the emergence ofdrug-resistant viral strains.

Drug resistance occurs when a disease no longer responds to atherapeutic treatment. For example, drug resistance can result frommutation of a gene, targeted by the antiviral drug, which is necessaryfor viral replication. The efficacy of an antiviral drug can beprolonged or restored by administering the antiviral compound incombination with a second component, such as a COX-2 inhibitor, asdescribed herein. The second component can induce additional,simultaneous stress on the virus, thus increasing the efficacy of thetherapeutic combination.

In one embodiment there is provided a method to treat a subjectsusceptible to or afflicted with fibromyalgia, the method comprisingadministering to the subject a therapeutically-effective combination ofan antiviral component and a COX-2 inhibitor component, wherein theamount of the antiviral component is administered in a total daily doserange from about 250 mg to about 2000 mg, and wherein the amount of theCOX-2 inhibitor component is administered in a total daily dose rangefrom about 15 mg to about 800 mg, and wherein the combinationadministered produces no substantial adverse event.

In another embodiment there is provided a method, as described herein,wherein the antiviral component is administered in a total daily doserange from about 250 mg to about 1000 mg.

In another embodiment there is provided a method, as described herein,wherein the antiviral component is administered in a total daily doserange from about 500 mg to about 2000 mg.

In another embodiment there is provided a method, as described herein,wherein the antiviral component is administered in a total daily doserange from about 400 mg to about 1600 mg.

In another embodiment there is provided a method, as described herein,wherein the COX-2 inhibitor component is administered in a total dailydose range from about 200 mg to about 800 mg.

In another embodiment there is provided a method, as described herein,wherein the COX-2 inhibitor component is administered in a total dailydose range from about 15 mg to about 30 mg.

In another embodiment there is provided a method, as described herein,wherein the COX-2 inhibitor component is administered in a total dailydose range from about 100 mg to about 150 mg.

In another embodiment there is provided a method, as described herein,wherein the antiviral component is administered in a daily dose of about500 mg, and wherein the COX-2 inhibitor component is administered in adaily dose of about 400 mg.

In one embodiment there is provided a method to treat a subjectsusceptible to or afflicted with one or more functional somatic syndromeconditions comprising: fibromyalgia, chronic fatigue syndrome, irritablebowel syndrome, chronic pain, chronic headache, chronic neck pain,chronic back pain, chronic depression, chronic clinical anxietydisorder, post-traumatic stress disorder (PTSD), brain fog, cognitivedysfunction and chronic interstitial cystitis, the method comprisingadministering to the subject a therapeutically-effective combination offamciclovir and celecoxib, wherein the amount of famciclovir isadministered in a total daily dose range from about 250 mg to about 1000mg, and wherein the amount of celecoxib is administered in a total dailydose range from about 200 mg to about 800 mg, and wherein thecombination administered produces no substantial adverse event.

In another embodiment there is provided a method, as described herein,wherein the condition is selected from the group consisting offibromyalgia, chronic fatigue syndrome, irritable bowel syndrome,chronic depression, chronic clinical anxiety disorder and chronicinterstitial cystitis.

In another embodiment there is provided a method, as described herein,wherein the condition is fibromyalgia.

In another embodiment there is provided a method, as described herein,wherein the condition is chronic fatigue syndrome.

In another embodiment there is provided a method, as described herein,wherein the condition is irritable bowel syndrome.

In another embodiment there is provided a method, as described herein,wherein the condition is a combination of fibromyalgia, chronic fatiguesyndrome and irritable bowel syndrome, coexistent in the subject.

In another embodiment there is provided a method, as described herein,wherein the amount of famciclovir is administered in a total daily doserange from about 250 mg to about 750 mg, and wherein the amount ofcelecoxib is administered in a total daily dose range from about 200 mgto about 500 mg.

In another embodiment there is provided a method, as described herein,wherein the amount of famciclovir administered in a total daily dose isabout 500 mg, and wherein the amount of celecoxib administered in atotal daily dose is about 400 mg.

E. Subjects

Suitable subjects to be treated according to the present inventioninclude mammalian subjects. Mammals according to the present inventioninclude, but are not limited to, human, canine, feline, bovine, caprine,equine, ovine, porcine, rodents, lagomorphs, primates, and the like, andencompass mammals in utero. Subjects may be of either gender and at anystage of development.

F. Combinations and Combination Therapy

The compounds of the present invention, an antiviral compound and aCOX-2 inhibitor, can be used as described herein or in combination withother pharmaceutically active compounds, to treat conditions such asthose previously described above. The compounds of the presentinvention, an antiviral compound and a COX-2 inhibitor, and otherpharmaceutically active compound(s) can be administered simultaneously(either in the same dosage form or in separate dosage forms) orsequentially. Accordingly, in one embodiment, the present inventioncomprises methods for treating a condition by administering to thesubject therapeutically-effective amounts of the compounds of thepresent invention, an antiviral compound and a COX-2 inhibitor, and oneor more additional pharmaceutically active compounds.

In another embodiment, there is provided a pharmaceutical compositioncomprising the compounds of the present invention, an antiviral compoundand a COX-2 inhibitor, one or more additional pharmaceutically activecompounds, and a pharmaceutically acceptable carrier.

In another embodiment, the one or more additional pharmaceuticallyactive compounds are administered in any order or even simultaneouslywith the compounds of the present invention, an antiviral compound and aCOX-2 inhibitor. If simultaneously, the multiple therapeutic agents areoptionally provided in a single, unified form, or in multiple forms (byway of example only, either as a single pill or as two or more separatepills).

EXAMPLES

The following example are merely illustrative, and do not limit thisdisclosure in any way.

Example A: Human Clinical Trials

Objective:

To explore the efficacy of the combination of celecoxib+famciclovir inthe treatment of patients diagnosed with one or more functional somaticsyndromes.

Study Design:

During the first week of treatment, a loading dose of 500 mg famciclovirtwice a day (BID) was employed, followed by a maintenance dose of 250 mgfamciclovir BID. The celecoxib dosage, 200 mg BID, remained constantthroughout treatment.

Patient Population and Diagnostic Criteria:

Patients selected were adult men and women, with a documented diagnosisof one or more functional somatic syndromes. Screening assessmentincluded a medical and psychological history and physical examination.

Nine distinct but related, and often-overlapping, conditions weretreated by the combination therapy described herein. The nine conditionsare:

1. Fibromyalgia

2. Irritable bowel syndrome

3. Chronic fatigue

4. Mood disorder/depression

5. Chronic anxiety disorder/PTSD

6. Chronic headache

7. Impaired cognition/brain fog

8. Interstitial cystitis

9. Chronic pain

Clinically, there is often observed overlap of each of these conditionswith one another in the typical patient. For example one rarely sees apatient with fibromyalgia without elements of chronic fatigue syndrome,chronic headaches, and mood disorders. Below are disease descriptionsand criteria used to diagnose these conditions:

1. Fibromyalgia-1990 ACR diagnostic criteria:

Pain on both sides of the body, above and below the waist In addition,axial skeletal pain (cervical spine, anterior chest, thoracic spine orlow back pain) must be present. Pain in 11 of 18 tender point sites ondigital palpation Digital palpation should be performed with anapproximate force of 4 kg. (Wolfe F. Smythe HA. et al. (1990) ArthritisRheum. 33, 160-172)

2. Irritable Bowel Syndrome

IBS is diagnosed when a person has abdominal pain or discomfort at leastthree times per month for the last 3 months without other disease orinjury that could explain the pain. The pain or discomfort of IBS mayoccur with a change in stool frequency or consistency or may be relievedby a bowel movement.

To meet the definition of IBS, the pain or discomfort should beassociated with two of the following three symptoms:

-   -   i) Start with bowel movements that occur more or less often than        usual    -   ii) Start with stool that appears looser and more watery or        harder and more lumpy than usual    -   iii) Improve with a bowel movement

-   (Kahn, et al. (2010) Nature Reviews Gastroenterology and Hepatology    7:565)

3. Chronic Fatigue Syndrome

Center for Disease Control Criteria for CFS diagnosis requires threecriteria:

-   -   i) The individual has had severe chronic fatigue for 6 or more        consecutive months that is not due to ongoing exertion or other        medical conditions associated with fatigue    -   ii) The fatigue significantly interferes with daily activities        and work    -   iii) The individual concurrently has 4 or more of the following        8 symptoms:        -   (a) post-exertion malaise lasting more than 24 hours        -   (b) unrefreshing sleep        -   (c) significant impairment of short-term memory or            concentration        -   (d) muscle pain        -   (e) pain in the joints without swelling or redness        -   (f) headaches of a new type, pattern, or severity        -   (g) tender lymph nodes in the neck or armpit        -   (h) a sore throat that is frequent or recurring

These symptoms should have persisted or recurred during 6 or moreconsecutive months of illness and they cannot have first appeared beforethe fatigue.

-   (Chronic fatigue syndrome: General information. Centers for Disease    Control and Prevention. http://www.cdc.gov/cfs/general)

4. Mood Disorder/Depression

DSM-IV Criteria for Major Depressive Disorder (MDD)

Diagnostic Criteria:

-   -   i) Depressed mood or a loss of interest or pleasure in daily        activities for more    -   than two weeks.    -   ii) Mood represents a change from the person's baseline.    -   iii) Impaired function: social, occupational, and educational.

Specific symptoms, at least 5 of these 9, present nearly every day:

-   -   i) Depressed mood or irritable most of the day, nearly every        day, as indicated by either subjective report (e.g., feels sad        or empty) or observation made by others.    -   ii) Decreased interest or pleasure in most activities, most of        each day.    -   iii) Significant weight change (5%) or change in appetite.    -   iv) Change in sleep: Insomnia or hypersomnia.    -   v) Change in activity: Psychomotor agitation or retardation.    -   vi) Fatigue or loss of energy.    -   vii) Guilt/worthlessness: Feelings of worthlessness or excessive        or inappropriate guilt.    -   viii) Concentration: diminished ability to think or concentrate.    -   iv) Suicidality: Thoughts of death or suicide, or has suicide        plan.

Beck Depression scale used to quantify level of depression (Beck, et al.(1961) Arch Gen Psychiatry 4, 561-571).

5. Chronic (Generalized) Anxiety Disorder/Post-Traumatic Stress Disorder(PTSD)

Diagnostic Criteria:

At least 6 months of “excessive anxiety and worry” about a variety ofevents and situations. Generally, “excessive” can be interpreted as morethan would be expected for a particular situation or event. Most peoplebecome anxious over certain things, but the intensity of the anxietytypically corresponds to the situation.

There is significant difficulty in controlling the anxiety and worry. Ifsomeone has a very difficult struggle to regain control, relax, or copewith the anxiety and worry, then this requirement is met.

The presence, for most days over the previous six months, of 3 or more(only 1 for children) of the following symptoms, which are not part ofanother mental disorder:

-   -   i) Feeling wound-up, tense, or restless    -   ii) Easily becoming fatigued or worn-out    -   iii) Concentration problems    -   iv) Irritability    -   v) Significant tension in muscles    -   vi) Difficulty with sleep

The symptoms cause “clinically significant distress” or problemsfunctioning in daily life. “Clinically significant” is the part thatrelies on the perspective of the treatment provider. Some people canhave many of the aforementioned symptoms and cope with them well enoughto maintain a high level of functioning.

The condition is not due to a substance or medical issue

(Anxiety disorders. In: Diagnostic and Statistical Manual of MentalDisorders DSM-IV-TR. 4th ed. Arlington, Va.: American PsychiatricAssociation; 2000. http://www.psychiatryonline.com)

6. Chronic Headache (HA)

International Headache Society Diagnostic Criteria:

In 1988 the International Headache Society published criteria for thediagnosis of a number of different headache types. This document wasupdated and published in 2004 (Cephalalgia 24 (Suppl. 1), 1-151).

Tension-Type Headache Diagnostic Criteria:

-   -   i) Headache lasting from 30 minutes to seven days.    -   ii) At least two of the following criteria:        -   (a) Pressing/tightening (non-pulsatile) quality        -   (b) Mild or moderate intensity (may inhibit, but does not            prohibit activity)        -   (c) Bilateral location        -   (d) No aggravation by walking, stairs or similar routine            physical activity    -   iii) Both of the following:        -   (a) No nausea or vomiting (anorexia may occur)        -   (b) Photophobia and phonophobia are absent, or one but not            both are present

Cervicogenic Headache Diagnostic Criteria:

-   -   i) Pain localized to the neck and occipital region. May project        to forehead, orbital region, temples, vertex or ears.    -   ii) Pain is precipitated or aggravated by special neck movements        or sustained postures.    -   iii) At least one of the following:        -   (a) Resistance to or limitation of passive neck movements.        -   (b) Changes in neck muscle contour, texture, tone or            response to active and passive stretching and contraction.        -   (c) Abnormal tenderness of neck muscles.    -   iv) Radiological examination reveals at least one of the        following:        -   (a) Movement abnormalities in flexion/extension        -   (b) Abnormal posture        -   (c) Fractures, congenital abnormalities, bone tumors,            rheumatoid arthritis or other distinct pathology (not            spondylosis or osteochondrosis)

7. Cognitive Dysfunction or Impairment

Cognitive dysfunction or impairment, also referred to as brain fog ormental fog, is the loss of intellectual functions (such as thinking,remembering, and reasoning) of sufficient severity to interfere withdaily functioning. Patients with cognitive dysfunction have trouble withverbal recall, basic arithmetic, and concentration.

Diagnostic Criteria:

Patient improvement was quantified using the Mental Clutter Scale(Leavitt, et al. (2011) Psychological Reports 109, 445-452).

8. Interstitial Cystitis

Diagnostic Criteria:

Diagnosis of interstitial cystitis is grounded in the symptomatology ofpelvic pain and urinary frequency that is of a chronic nature andunexplained by any known urologic or other system pathology (P. Hanno(2002) Rev. Urol. 4(Suppl. 1): S3-S8.

9. Chronic Pain

Chronic pain generally refers to persistent, non-acute, sometimesdisabling pain in the extremities or other areas of the body. The paincan be associated with a known cause such as a major or minor injury, orit can be a symptom of a painful chronic condition such as fibromyalgia.It can just as often be of unknown origin. The term chronic pain canrefer to pain that has been present for an arbitrarily defined period,for example, longer than 6 months. Alternatively, the term “chronicpain” is often used as a synonym for the term “chronic pain syndrome,” adescriptive term used to indicate persistent pain, subjective symptomsin excess of objective findings, associated dysfunctional painbehaviors, and self-limitation in activities of daily living. Chronicpain syndrome (CPS) is the presentation of combined physical andpsychological changes due to chronic pain.

Patients classified with chronic pain fit the 6 criteria blow:

-   -   i) Dramatization of complaints    -   ii) Drug misuse    -   iii) Dysfunction    -   iv) Dependency    -   v) Depression    -   vi) Disability

Results:

The results, presented in the table below, are based on patientsresponse to a visual analogue scale (VAS) for pain (Hurst, et al. (2004)J. Manip. Physiol. Therap. (JMPT) 27, 26-35). Individual valuesrepresent improvement on a scale from 1-7 as follows: 1—no change orcondition has worsened; 2—Almost the same, hardly any change; 3—A littlebetter, but the change has not made any real difference; 4—Somewhatbetter, but the change has not made any real difference; 5—Moderatelybetter, and a slight but noticeable change; 6—Better, and a definiteimprovement that has made a real and worthwhile difference; 7—A greatdeal better, and a considerable improvement that has made all thedifference.

Patients showing a % Pain Improvement of >30% are considered clinicallyresponsive to the therapy.

TABLE A Clinically - Treated Patient Responses Patient ID A B C D E F GH I J K L M N 01-9221 84 7.0 2.0 FM 71.4% 7 3 6 02-9218 94 10.0 4.0Brian Fog 60.0% 7 6 7 7 03-9046 223 n/a n/a Chronic n/a 3 3 Anxiety04-9122 162 10.0 2.0 FM 80.0% 7 7 7 6 05-9284 43 5.5 4.0 FM 27.3% 5 4 606-9013 239 8.0 5.0 IBS 37.5% 6 5 07-7135 49 8.0 2.0 Chronic 75.0% 6 7 7Pain 08-9164 114 n/a n/a IBS n/a 6 7 6 7 09-8926 169 7.0 0.0 CFS 100.0% 7 7 7 10-9222 88 10.0 5.0 FM 50.0% 5 4 6 6 11-9118 56 8.0 6.0 Chronic25.0% 2 4 Pain 12-9203 105 8.0 5.0 FM 37.5% 6 5 4 4 13-9195 105 8.0 7.0FM 12.5% 2 1 3 1 14-9199 106 10.0 3.0 IBS 70.0% 7 6 7 7 5 15-9243 7010.0 2.0 FM 80.0% 7 4 16-9314 31 8.0 3.0 CFS 62.5% 6 4 17-9209 101 10.07.0 FM 30.0% 4 1 4 7 1 18-9227 86 10.0 0.0 FM 100.0%  6 3 3 6 19-9312 30n/a n/a Brain Fog n/a 2 3 20-9196 63 8.5 2.5 Chronic 70.6% 7 7 6 7 Pain21-9208 100 8.0 7.0 CFS 12.5% 3 4 3 22-9252 87 9.0 4.0 CFS 55.6% 4 4 628-8043 132 7.0 4.0 FM 42.9% 4 4 1 1 2 6 39-9138 142 10.0 7.0 FM 30.0% 31 3 1 2 3 41-9207 113 8.5 2.0 FM 76.5% 5.5 2 7 2 Legend: A: Length ofTreatment (Days), B: Pain Initial VAS, C: Pain Follow-Up VAS, D:Predominant Disease, E: Pain Improvement, F: Fibromyalgia, G: CognitiveDysfunction/Brain Fog, H: Chronic Anxiety Disorder/PTSD, I: ChronicPain, J: Chronic Fatigue, K: Chronic Headache, L: Interstitial Cystitis,M: Mood disorder/Depression, N: IBS. (n/a: not available)

Example B: Human Clinical Trial Protocol (PRID-201)

TITLE: A Double-Blinded, Randomized, Placebo-Controlled, Proof ofConcept Phase 2a Study Exploring the Safety and Efficacy ofFamciclovir+Celecoxib in the Treatment of Patients with Fibromyalgia.

OBJECTIVE: To explore the safety and efficacy of the combination ofcelecoxib+famciclovir vs. placebo in the treatment of fibromyalgia (FM).

Study Design:

Randomized, double-blind, placebo-controlled, 16-week study to evaluatethe safety and efficacy of famciclovir and celecoxib combination for thetreatment of FM patients. During the first week of treatment, a loadingdose of famciclovir (2× maintenance dose) twice a day (BID) will beemployed, followed by 15 weeks of maintenance dose of famciclovir BID.Depending on the patient population of the study group, use of a loadingdose greater than 1000 mg/day is optional. The celecoxib dosage (alsoBID) will remain constant throughout the 16 weeks of active treatment.

Patients will be randomized to treatment with either combination therapyor placebo.

Qualified patients will have primary FM (defined by the 2010 AmericanCollege of Rheumatology diagnostic criteria for FM [Wolfe, et al. (2010)Arthritis Care & Res. 62(5), 600-610], and an absence of other sourcesof significant pain related to systemic auto-immune diseases, structuralor traumatic rheumatic conditions, or other conditions that couldcompromise the interpretation of study results.

Patients will undergo initial screening procedures, after which theyproceed with the washout of excluded medications, if required. Patientsdependent upon opioids or narcotics for pain control should not beenrolled in the study.

Due to the celecoxib component, patients will discontinue regular use ofall other non-steroidal anti-inflammatory drugs (NSAIDs) at the time ofrandomization. Acetaminophen may be utilized throughout the study atdoses not to exceed 3250 mg per day. Patients may also continue low-doseaspirin for cardioprotection (<325 mg/day), triptans and ergotamines formigraine, and dopaminergic agents for restless leg syndrome, as well asmuscle relaxants, sleeping aids and benzodiazepines (assuming noevidence of abuse or dependency). Tramadol may be utilized as a rescuetherapy for severe flares of FM or other acutely painful conditions(e.g., injury; procedure-related pain). Tramadol should not be takenwithin 48 hours of the Week 2, 6 and 12 study visits, or within 7 daysof the Baseline and Week 16 visits.

Metabolic profiles of each patient's concomitant medications should beassessed to ensure there is no risk of significant drug-druginteractions with either drug. For drugs that are metabolized by CYP2C9,the concomitant use of fluconazole—a potent CYP2C9 inhibitor—should beavoided.

Patients will not be allowed to take duloxetine, milnacipran, pregabalinand sodium oxybate during the trial, and a seven day washout intervalprior to randomization is required. In addition, to qualify for thestudy, each patient's 24 hour recall pain score must be between 40 and90 on a 100 mm visual analog scale (VAS) at the screening visit andbetween 4 and 9 on a numerical rating scale (NRS) at the Baseline visit.

After ensuring that all entry criteria have been satisfied and washoutsuccessfully completed, patients will return for baseline assessmentsand randomization. The day of the baseline assessments will be referredto as Day 0; patients will initiate study drug either with the eveningdose on Day 0 or the morning dose on the following day (Day 1),continuing with BID treatment for the duration of the study.

Blood will be collected at the screening visit for safety assessmentsand for exploratory cytokine analyses (e.g., IL-1β, IL-4, IL-6, IL-8,IL-10, TNF-α, IFN-α, IFN-β, IFN-γ). A second sample for cytokineanalyses will also be obtained at the Baseline/randomization visit.Follow-up blood sampling for safety and cytokine analyses will takeplace at the Week 6 and 16 visits (or at the time of early termination).A standard urinalysis panel will be included as part of the safety labscollected at screening, Week 6 and Week 16.

Study drugs will be over-encapsulated to maintain the double-blind, andactive and placebo patients will receive identical-appearing supplies ofstudy drug. Study drug will be provided in 2-week bottles; therefore,patients will receive 1, 2, or 3 separate bottles of each drug (ormatching placebo) at every study visit, depending on the number of weeksuntil the next scheduled visit. For the first week only, the patientwill receive a third bottle which contains additional famciclovir toprovide a one week loading dose. Patients will take one capsule BID(with meals) from each of the 3 bottles assigned for the first week,followed by one capsule BID from each of the 2 bottles provided forsubsequent weeks. Patients will receive study drug treatment for a totalof 16 weeks, with study visits during the active treatment phase of thestudy scheduled for Weeks 2, 6, 12 and 16, or early termination (ET).

Inclusion Criteria:

-   -   1. Willing and able to read, understand, and sign the informed        consent.    -   2. Male or female, 18-70 years of age, inclusive.    -   3. Each female patient must have a negative urine pregnancy test        at Screening and Baseline unless she is post-menopausal.    -   4. Females of child-bearing potential must be willing to utilize        an effective birth control method for the duration of their        study participation.    -   5. Diagnosis of primary FM.    -   6. In the opinion of the Investigator, the patient is willing        and able to comply with all protocol-specified requirements

Exclusion Criteria:

-   -   1. Breastfeeding or pregnant.    -   2. Investigational drug usage within 30 days of Screening.    -   3. Diagnosed with failed back syndrome, infectious arthritis,        rheumatoid arthritis, systemic lupus erythematosis, or other        systemic auto-immune diseases.    -   4. In the opinion of the Investigator, any clinically        significant, uncontrolled or unstable medical, psychiatric or        surgical condition that could affect the patient's ability to        participate in the study or potentially compromise his/her        well-being while enrolled in the study.    -   5. Current systemic infection (e.g., HIV, hepatitis).    -   6. History of significant adverse reaction or allergy to study        drugs.    -   7. In the opinion of the Investigator, evidence of clinically        significant laboratory abnormality(ies) based on the results of        the screening laboratory assessments and/or medical history.

Study Drugs:

The individual study drugs being evaluated in combination, as describedherein, have been extensively studied individually in humans as well asanimals. The doses and duration of treatment to be evaluated in thesestudies are consistent with each individual drug's current FDA-approvedproduct labeling.

Study drug will be blinded by over-encapsulation of medications. Eachmedication will be provided in a separate bottle and clearly labeled ina blinded fashion. Placebo will be provided in capsules and bottlesidentical to those used for active study drug. All patients will takeone capsule from each assigned bottle twice daily, with meals.

The Patient Groups and treatments for the study are summarized below:

Patient Treatment Groups

TABLE B Famciclovir + Celecoxib TOTAL DAILY TOTAL DAILY LOADING DOSEMAINTENANCE (mg) DOSE (mg) GROUP DRUG (Week 1) (Weeks 2-16) PlaceboFamciclovir 0 0 Celecoxib 0 0 A Famciclovir 500 250 Celecoxib 200 200 BFamciclovir 500 250 Celecoxib 400 400 C Famciclovir 500 250 Celecoxib800 800 D Famciclovir 1000 500 Celecoxib 200 200 E Famciclovir 1000 500Celecoxib 400 400 F Famciclovir 1000 500 Celecoxib 800 800 G Famciclovir2000 1000 Celecoxib 200 200 H Famciclovir 2000 1000 Celecoxib 400 400 IFamciclovir 2000 1000 Celecoxib 800 800

In addition, further studies will be performed, either simultaneously orsubsequent to the combination studies described above, consistent withFDA “Draft Guidance for Industry: Codevelopment of Two or MoreUnmarketed Investigational Drugs for Use in Combination” (December2010). Specifically, studies will be employed to determine thecontributions of the individual drugs used in combination. By way ofexample, a four-arm factorial study design may be used to compareresults from the combination therapy to individual components andplacebo (e.g., A+B v. A v. B v. placebo). These comparative studies,when done subsequent to the dose-ranging studies described herein, willutilize doses that produced the best results, while comparative studiesdone simultaneously may utilize multiple doses, possibly favoring thehigher range of doses.

Results:

Efficacy Measures

-   -   The primary outcome measure will be the patient's self-reported        24-hour recall average pain severity, evaluated on an 11 point        numerical rating scale (NRS).    -   Secondary measures will include:        -   Patient's self-reported Global Impression of Change (PGIC)        -   Revised Fibromyalgia Impact Questionnaire (FIQ-R)    -   Exploratory measures will include:        -   Changes in cytokines associated with inflammation and/or            viral infection        -   NIH Patient Reported Outcomes Measurement Information System            (PROMIS) fatigue questionnaire        -   Multi-Dimensional Fatigue Inventory (MFI-20)        -   Beck Depression Inventory (BDI-II)

Safety Measures

Safety measures include vital signs (sitting blood pressure and heartrate, oral temperature, weight), adverse events and clinical laboratoryassessments.

Statistical Analyses:

The primary efficacy assessment for the determination of therapeuticefficacy will be the change from baseline in the 24-hour recall painscore as recorded on the 11-point NRS over 16 weeks of treatment. Changefrom baseline will be determined by comparing the baseline 24 hourrecall pain score to that determined at Weeks 6, 12 and 16/ET.

The mean change from baseline in the combination drug treatment groupswill be compared to that determined for the placebo treatment group over16 weeks of treatment using a mixed model repeated measures (MMRM). Thenull hypothesis will be that there is no difference between treatmentgroups in terms of the mean change from baseline. Rejection of thishypothesis will indicate efficacy of the combination therapy.

All mentioned documents are incorporated by reference as if hereinwritten. When introducing elements of the present invention or theexemplary embodiment(s) thereof, the articles “a,” “an,” “the” and“said” are intended to mean that there are one or more of the elements.The terms “comprising,” “including” and “having” are intended to beinclusive and mean that there may be additional elements other than thelisted elements. Although this invention has been described with respectto specific embodiments, the details of these embodiments are not to beconstrued as limitations.

What is claimed is:
 1. A fixed-dose drug combination comprising anantiviral nucleoside analog and a COX-2 inhibitor, wherein the antiviralnucleoside analog is famciclovir and is present in a unit dosage form toprovide a total daily dose in a range from about 500 mg to about 2000mg, and wherein the COX-2 inhibitor is celecoxib and is present in aunit dosage form to provide a total daily dose in a range from about 300mg to about 400 mg, and wherein the amounts of famciclovir and celecoxibin the fixed-drug combination are synergistically effective forfibromyalgia pain relief.
 2. The fixed-dose drug combination of claim 1,wherein the famciclovir is present in a unit dosage form from about 125mg to about 500 mg.
 3. The fixed-dose drug combination of claim 1,wherein the famciclovir is present in a unit dosage form from about 500mg to about 1000 mg.
 4. The fixed-dose drug combination of claim 1,wherein the famciclovir is present in a unit dosage form of about 250 mgor about 500 mg.
 5. The fixed-dose drug combination of claim 1, whereinthe celecoxib is present in a unit dosage form from about 100 mg toabout 400 mg.
 6. The fixed-dose drug combination of claim 1, wherein thecelecoxib is present in a unit dosage form selected from the groupconsisting of about 100 mg, about 200 mg, and about 400 mg.
 7. Thefixed-dose drug combination of claim 6, wherein the celecoxib is presentin a unit dosage form of about 200 mg.
 8. The fixed-dose drugcombination of claim 7, wherein the famciclovir is present in a unitdosage form from about 500 mg to about 1000 mg.
 9. A method for treatingfibromyalgia pain, the method comprising: administering to a patient inneed of fibromyalgia pain relief a fixed-dose drug combination whereinthe antiviral nucleoside analog is famciclovir and is present in a unitdosage form to provide a total daily dose in a range from about 500 mgto about 2000 mg, and wherein the COX-2 inhibitor is celecoxib and ispresent in a unit dosage form to provide a total daily dose in a rangefrom about 300 mg to about 400 mg, and wherein the amounts offamciclovir and celecoxib in the fixed-drug combination aresynergistically effective for fibromyalgia pain relief.
 10. The methodof claim 9, wherein the famciclovir is present in a unit dosage formfrom about 125 mg to about 500 mg.
 11. The method of claim 9, whereinthe famciclovir is present in a unit dosage form from about 500 mg toabout 1000 mg.
 12. The method of claim 9, wherein the famciclovir ispresent in a unit dosage form of about 250 mg or about 500 mg.
 13. Themethod of claim 9, wherein the celecoxib is present in a unit dosageform from about 100 mg to about 400 mg.
 14. The method of claim 9,wherein the celecoxib is present in a unit dosage form selected from thegroup consisting of about 100 mg, about 200 mg, and about 400 mg. 15.The method of claim 14, wherein the celecoxib is present in a unitdosage form of about 200 mg.
 16. The method of claim 15, wherein thefamciclovir is present in a unit dosage form from about 500 mg to about1000 mg.